The American Urological Association and the American Society for Reproductive Medicine report that ~15% of couples (i.e., more than 6.1 million people in the U.S.) experience infertility at some time. The male is responsible for infertility of 20% of these couples and contributes to the infertility of another 30-40%. However, the cause(s) of male infertility in many cases is unknown. Our data suggest that lead exposures (in the air, in food and in drinking water) underlie a significant fraction of "unexplained" male infertility. We found that blood and seminal plasma lead levels were elevated in 22% of normospermic males from couples seeking infertility treatment, in 29% of semen donors participating in an artificial insemination program and in 23% of unselected semen donors answering an advertisement for research participation. These elevated lead levels were associated with decreased sperm fertility potential in IVF, in artificial insemination and in pregnancy by coitus. The negative effects of lead on sperm function was correlated with expression of specific forms of sperm ion channels (metal binding proteins that allow lead to enter cells), suggesting that such proteins serve as markers for susceptibility or resistance to the reproductive toxic effects of lead. Further, in cases in which human male lead levels changed markedly over time, there were corresponding changes in sperm ion channel, sperm function and sperm fertility potential. These changes were linked to changes in calcium modulated processes in human testis biopsies obtained from infertility patients and could be mimicked in testes of rats experimentally fed lead.